Biochemical Journal最新文献_第2页

Oligomeric assemblies of plant biotin carboxylase revealed by cryo-EM and cross-linking. 低温电镜和交联技术揭示植物生物素羧化酶的低聚体。

IF 4.3 3区生物学

Biochemical Journal Pub Date : 2026-05-06 DOI: 10.1042/BCJ20250372

Hunter J Madison, Luke Dunn, Youngki You, Gabriel Lemes Jorge, Ljiljana Paša-Tolić, Jay J Thelen, Steven R Van Doren, Adam L Yokom

{"title":"Oligomeric assemblies of plant biotin carboxylase revealed by cryo-EM and cross-linking.","authors":"Hunter J Madison, Luke Dunn, Youngki You, Gabriel Lemes Jorge, Ljiljana Paša-Tolić, Jay J Thelen, Steven R Van Doren, Adam L Yokom","doi":"10.1042/BCJ20250372","DOIUrl":"10.1042/BCJ20250372","url":null,"abstract":"<p><p>Due to the interest in fatty acid synthesis by oilseed crops, we conducted structural studies of the biotin carboxylase (BC) subunit of the plastid acetyl-CoA carboxylase (ACCase). ACCase catalyzes the first committed step in the fatty acid synthesis pathway and is highly regulated. Cryo-electron microscopy revealed that Thlaspi arvense (pennycress) BC forms a symmetric dimer and contains a subpopulation of a dimer-of-dimers. The domain of BC that closes over the catalytic cleft (the B-domain) appears to be dynamic, judging from the B-factors, normal mode analysis of BC structures, and its high susceptibility to acetylation. An increase in the BC concentration decreased the reactivity of the B-domain, however, suggesting structural hindrance. The partial protection of the B-domain was consistent with cross-links that formed between dimers of BC using a cross-linker cleavable in the mass spectrometer. Cross-links guided HADDOCK docking calculations suggesting a dimer of dimers of BC that is asymmetric, staggered, and tilted between dimers, with conservation in the interface. In contrast, a minimal population of a symmetric dimer of dimers with a small, non-conserved interface was observed by cryo-electron microscopy. Taken together, our structural models are the first for Brassicaceae family BC homologs and are the first from plants. These models suggest dimer interactions that might contribute to larger oligomers of BC and influence associations with other subunits of the heteromeric ACCase.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"803-817"},"PeriodicalIF":4.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13142922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Target discrimination and PAM profiling of the Thermotoga maritima type I-B CRISPR system. 海洋热藓I-B型CRISPR系统的靶向识别和PAM谱分析。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-28 DOI: 10.1042/bcj20260189

John Mallon,Charles J Lenihan,Sowmyaa Shridhar,Scott Bailey

{"title":"Target discrimination and PAM profiling of the Thermotoga maritima type I-B CRISPR system.","authors":"John Mallon,Charles J Lenihan,Sowmyaa Shridhar,Scott Bailey","doi":"10.1042/bcj20260189","DOIUrl":"https://doi.org/10.1042/bcj20260189","url":null,"abstract":"Type I-B CRISPR-Cas systems represent the most abundant CRISPR subtype in nature and have emerged as powerful tools for endogenous genome editing in diverse prokaryotes. Here we reconstitute and characterize the type I-B1 system from the thermophile Thermotoga maritima (Tma) using purified components. We demonstrate that Tma Cascade requires standalone Cas11 expression, as the cryptic internal translation start site within cas8b1 is non-functional in E. coli. The reconstituted system exhibits canonical type I function including RNA-guided DNA binding, PAM-dependent target discrimination, Cas3-mediated degradation, and seed region interrogation spanning seven PAM-proximal nucleotides. Using next-generation sequencing-based PAM library screens, we define a YYD consensus PAM (Y = C/T; D = G/A/T) with strong discrimination against the array repeat-adjacent sequence (AAC). Comprehensive PAM profiling reveals context-dependent tolerance for non-consensus sequences and identifies numerous intermediate-activity PAMs that may function in priming. Comparison with other characterized type I-B systems reveals correlation between Cas8b variant and position -3 specificity, conserved pyrimidine preference at position -2, and variability at position -1. This work establishes a thermostable type I-B platform for biotechnological applications and provides insights into evolutionary mechanisms balancing PAM promiscuity with self-discrimination in the most abundant CRISPR-Cas subtype.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"154 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of essential residues for the biosynthesis of momilactone intermediate diterpene in wild rice Oryza officinalis. 野生稻米内酯中间体二萜生物合成必需残留物的鉴定。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-27 DOI: 10.1042/bcj20250321

Yuto Hasegawa,Yoshitaka Moriwaki,Yuri Takeda-Kimura,Kazunori Okada,Tomonobu Toyomasu

{"title":"Identification of essential residues for the biosynthesis of momilactone intermediate diterpene in wild rice Oryza officinalis.","authors":"Yuto Hasegawa,Yoshitaka Moriwaki,Yuri Takeda-Kimura,Kazunori Okada,Tomonobu Toyomasu","doi":"10.1042/bcj20250321","DOIUrl":"https://doi.org/10.1042/bcj20250321","url":null,"abstract":"It is well-known that momilactones are diterpenoids that play important roles in the survival strategy of cultivated rice (Oryza sativa). Momilactones serve not only as phytoalexins against pathogens but also as allelopathic substances against other plant species. It has been reported that several wild rice species also produce momilactones. Among them, the CC genome species Oryza officinalis possesses two homologs of the diterpene synthase OsKSL4, which is responsible for momilactone biosynthesis; OoKSL4-1 and OoKSL4-2. Diterpene synthases have a role in constructing specific carbon skeletons in diterpenoid biosynthetic pathways. Previously, it was reported that OoKSL4-2, but not OoKSL4-1, converts syn-copalyl diphosphate to 9β-pimara-7,15-diene, the biosynthetic intermediate diterpene of momilactones. We herein identified residues that are required for the production of 9β-pimara-7,15-diene by comparing the sequences of OoKSL4-1 and OoKSL4-2. Amino acid substitution experiments reveal that the product profile of the triple substitution mutant OoKSL4-1-I592L/R700G/I702T was almost identical to that of OoKSL4-2, with converse mutagenesis further indicating that 585L, 693G and 695T in OoKSL4-2 are important for the production of 9β-pimara-7,15-diene. Protein-ligand structure predictions suggest that the OoKSL4-1 triple mutant and OoKSL4-2 bind the substrate in a similar orientation within the binding pocket, positioning the two carbon atoms involved in the cyclization reaction close together. In contrast, wild-type OoKSL4-1 binds the substrate in a different orientation, resulting in a greater distance between the two carbons. This difference in the distance is well correlated with more efficient production of 9β-pimara-7,15-diene by OoKSL4-2 compared with OoKSL4-1.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"151 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure and function of the L-MYC N-terminus impacts strategies to inhibit the MYC family of oncoproteins. L-MYC n端结构和功能影响抑制MYC家族癌蛋白的策略。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-24 DOI: 10.1042/bcj20260054

Tristan Mg Kenney,Scott Houliston,Peter Lin,Nikan Movahedi,Cheryl Arrowsmith,Linda Z Penn

{"title":"Structure and function of the L-MYC N-terminus impacts strategies to inhibit the MYC family of oncoproteins.","authors":"Tristan Mg Kenney,Scott Houliston,Peter Lin,Nikan Movahedi,Cheryl Arrowsmith,Linda Z Penn","doi":"10.1042/bcj20260054","DOIUrl":"https://doi.org/10.1042/bcj20260054","url":null,"abstract":"The MYC family of transforming oncogenes function as regulators of gene transcription and is composed of three members, MYC, MYCN and MYCL. As c-MYC (MYC) is deregulated in >50% of human cancers, the role, regulation and structural features of MYC have been well-studied. By contrast, L-MYC has been understudied as historically, oncogenic deregulation was evident only in a subset of lung carcinomas. However, recent deep genomic analyses of primary patient samples has demonstrated that L-MYC is deregulated in numerous human cancers. With this revelation it is important to understand how L-MYC compares to MYC at the structural level, particularly for the development of broad-spectrum inhibitors of the MYC family. Here we show that L-MYC expression is elevated in several primary patient tumor samples, providing further evidence for L-MYC as a driver oncoprotein in primary human cancers. Next, we provide new biophysical insights into an N-terminal region within the L-MYC transactivation domain, which harbors two regions conserved amongst MYC proteins: MYC box 0 (MB0) and MYC box I (MBI). NMR spectroscopy of residues 1-80 of L-MYC confirms that it is largely intrinsically disordered and interacts with the known MYC-MB0 interactor, PNUTS (Phosphatase 1 NUclear Targeting Subunit). Comparatively, L-MYC does not interact with the MYC-MBI interactor and tumor suppressor Bin1 (Bridging integrator 1). Together, these results further substantiate the oncogenic role of L-MYC in human cancer and enhance our understanding of the biophysical nature of L-MYC to improve strategies for the development of anti-cancer therapeutics targeting MYC family members.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"20 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147739093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BMP4 signaling regulates the expression of signals and transcription factors for coordinated cytodifferentiation in the murine ureter. BMP4信号传导调节小鼠输尿管中协调细胞分化的信号和转录因子的表达。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-22 DOI: 10.1042/bcj20260126

Lena Deuper,Nicolas Hense,Anja Beckers,Hauke Thiesler,Tamrat M Mamo,Florian Bergmann,Herbert Hildebrandt,Mark-Oliver Trowe,Andreas Kispert

{"title":"BMP4 signaling regulates the expression of signals and transcription factors for coordinated cytodifferentiation in the murine ureter.","authors":"Lena Deuper,Nicolas Hense,Anja Beckers,Hauke Thiesler,Tamrat M Mamo,Florian Bergmann,Herbert Hildebrandt,Mark-Oliver Trowe,Andreas Kispert","doi":"10.1042/bcj20260126","DOIUrl":"https://doi.org/10.1042/bcj20260126","url":null,"abstract":"Mutations in BMP4 have been associated with malformations of the urinary tract in human patients. Genetic studies in mice have shown that these defects are linked to the expression of Bmp4 in the mesenchymal primordium of the ureter, where it acts as a critical signal for coordinated cytodifferentiation of the mesenchymal and epithelial tissues. Here, we used unbiased transcriptional profiling of ureters with genetic depletion of Bmp4 and pharmacological inhibition of BMP4 signaling to decipher the gene regulatory network controlled by BMP4 in the early ureter, focusing on transcription factors as possible drivers of cytodifferentiation. We show that in Bmp4-deficient ureters, expression of Grhl3, Msx2, Pparg, Trp63 and Foxa1 in the epithelial compartment, and of Gata6, Hopx, Id2, Id4, Myocd, Snai1 and Tbx18 in the mesenchymal primordium is reduced. Expression of Msx2, Pparg, Gata6, Id genes, Tbx18 and Snai1 requires direct BMP4 signaling input, whereas reduced expression of the other genes is likely due to secondary changes, including increased retinoic acid signaling. Conditional gene targeting of Smad4 revealed that BMP4-dependent activation of transcription factor genes is mediated in part by SMAD effectors in both ureteral tissues. Thus, our work links BMP4 (signaling) to known transcriptional regulators of ureteral cytodifferentiation and uncovers additional factors that may be relevant to this program.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"143 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combination amino acids and glucose effects on insulin and GLP-1 secretion. 氨基酸和葡萄糖对胰岛素和GLP-1分泌的影响。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-21 DOI: 10.1042/bcj20253316

Kenneth H C Koh,Junhe Zhao,Sarah X Luo,Yusuf Ali,Wei Ning Chen,James C Y Chan

{"title":"Combination amino acids and glucose effects on insulin and GLP-1 secretion.","authors":"Kenneth H C Koh,Junhe Zhao,Sarah X Luo,Yusuf Ali,Wei Ning Chen,James C Y Chan","doi":"10.1042/bcj20253316","DOIUrl":"https://doi.org/10.1042/bcj20253316","url":null,"abstract":"Dietary nutrients such as amino acids possess an insulinogenic effect. However, not all amino acids were meticulously investigated for their effect on both insulin and incretin secretion, and the effect of amino acids given in different combinations remained incompletely characterized. In this work, we reported the quantitative effect of individual and combinatorial amino acids in conjunction with low and high glucose respectively on insulin secretion from human islets and on GLP-1 secretion from secretin tumour cell (STC-1). STC-1 cells were incubated with amino acid treatment solutions individually and in combinations at low and high glucose to investigate GLP-1 secretion. Batches of 15 islets were sequentially treated with 3 mM glucose, combinatorial amino acid treatment solutions at low and high glucose and finally 25 mM KCl to quantify insulin secretion. Lysine, threonine, tryptophan, phenyalalnine and aspartic acid significantly increased GLP-1 secretion in STC-1 cells compared to negative control. Branched-chain amino acids (BCAA) stimulated greater GLP-1 secretion only at high glucose and significantly induce insulin secretion in islets even in low glucose. Other amino acid combinations tested were able to augment GLP-1 secretion even in the absence of glucose but failed to further stimulate insulin secretion in human islets when given concurrently at higher glucose concentrations. In conclusion, the findings from our work could be used to infer the expected insulinogenic effect and glycaemic response for proteins with different amino acids compositions.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"96 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional interaction surfaces of the bacterial transcription terminator Rho are required for the interactions with the elongation factor NusG. 细菌转录终止子Rho的功能相互作用表面是与延伸因子NusG相互作用所必需的。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-17 DOI: 10.1042/bcj20250320

Abhijeet Behera,Passong Immanual R Chhakchhuak,Sriyans Jain,Ranjan Sen

{"title":"Functional interaction surfaces of the bacterial transcription terminator Rho are required for the interactions with the elongation factor NusG.","authors":"Abhijeet Behera,Passong Immanual R Chhakchhuak,Sriyans Jain,Ranjan Sen","doi":"10.1042/bcj20250320","DOIUrl":"https://doi.org/10.1042/bcj20250320","url":null,"abstract":"Transcription terminator Rho interacts with the elongation factor NusG to induce efficient termination. By employing random mutagenesis, structure-guided site-directed mutagenesis, and phenotypic re-evaluations of our laboratory mutants, we identified several mutations in the Rho-linker region (~135-155) and the hydrophobic pocket (200-230), in addition to those observed in the CTD region (>250). These mutants exhibited synthetic growth defects and in vivo termination defects in the presence of the NusG-CTD mutant G146D, which is defective for Rho binding. Mutants from the Rho-CTD (I382A and I382N) were the most defective for NusG binding; however, mutants from the linker (E148R) and hydrophobic pocket (P167L) were also significantly impaired. These mutants did not respond properly to NusG in the in vitro transcription reactions. Fluorescence quenching assays showed that in presence of NusG, single-cysteine derivatives at 166C (near the linker), 202C (hydrophobic pocket) and at 325C (Rho-CTD) were buried from the surface, whereas that at 80C remained exposed to the solvent. A unique mutation of Rho, H256Y, residing near the Rho-hydrophobic patch defined the pathway of Rho-CTD to its NTD conformational changes upon binding to NusG. We propose that NusG-CTD - Rho-CTD induces a conformational change pathway to the latter's NTD to accelerate Rho-close complex formation upon binding to the rut sites.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"88 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147694909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A metabolite extracted from E. coli suppresses tau aggregation. 从大肠杆菌中提取的代谢物抑制tau聚集。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-15 DOI: 10.1042/bcj20260068

Mahalashmi Srinivasan,Akhil Patel,Tark Patel,Jack Moore,Erik Gomez-Cardona,Allan Yarahmady,Brian D Sykes,Olivier Julien,Sue-Ann Mok

引用次数: 0

Influence of SmpB and ClpX interactions and interactomes on the transcription profile of Mycobacterium tuberculosis. SmpB和ClpX相互作用及相互作用组对结核分枝杆菌转录谱的影响。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-13 DOI: 10.1042/bcj20253192

Ashish Deshmukh,Sidra Khan,Amit Chakraborty,Vinay Nandicoori,Balasubramanian Gopal

{"title":"Influence of SmpB and ClpX interactions and interactomes on the transcription profile of Mycobacterium tuberculosis.","authors":"Ashish Deshmukh,Sidra Khan,Amit Chakraborty,Vinay Nandicoori,Balasubramanian Gopal","doi":"10.1042/bcj20253192","DOIUrl":"https://doi.org/10.1042/bcj20253192","url":null,"abstract":"SmpB is a key regulator of trans-translation in bacteria. The interactome of Mycobacterium tuberculosis (Mtb) ClpX revealed SmpB alongside multiple transcriptional regulators and sigma factors that can alter the transcriptional profile. The finding that ClpX could also be identified in the Mtb SmpB interactome suggested both physical and functional linkages between trans-translation and targeted protein degradation. The trans-translation mechanism facilitates the release of stalled ribosomes and the attachment of ssrA degron sequences to aberrant proteins. We show that both SmpB and the previously described Mtb ClpX adaptor, SSB, bind to the N-terminal domain of ClpX. However, unlike the adaptor SSB, SmpB binding does not enhance ClpX ATPase activity. Interaction studies using a model substrate with an exposed ssrA degron revealed that SmpB enhances ClpX-substrate interactions. ClpX unfoldase activity, on the other hand, enables targeted degradation of proteins containing the ssrA degron. ClpX also facilitates the release of specific s factors from inactive sigma/anti-sigma complexes by degrading anti-sigma factors containing the ssrA degron thus indirectly influencing the transcription profile. Together, these observations suggest that SmpB and ClpX interactions and interacting protein networks exert both direct as well as indirect effects on the Mtb transcriptional profile.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"9 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147680639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dapagliflozin regulates autophagy in nephropathy associated with non-diabetic obesity via elevated plasma β-hydroxybutyrate levels. 达格列净通过提高血浆β-羟基丁酸水平调节非糖尿病性肥胖相关肾病的自噬。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2026-04-08 DOI: 10.1042/bcj20240504

Yan Kong,Xiaoyue Peng,Wenying Fan,Li Zhang,Yijie Wu,Miaoyan Zheng,Chunyan Shan

{"title":"Dapagliflozin regulates autophagy in nephropathy associated with non-diabetic obesity via elevated plasma β-hydroxybutyrate levels.","authors":"Yan Kong,Xiaoyue Peng,Wenying Fan,Li Zhang,Yijie Wu,Miaoyan Zheng,Chunyan Shan","doi":"10.1042/bcj20240504","DOIUrl":"https://doi.org/10.1042/bcj20240504","url":null,"abstract":"Obesity is a major contributor to chronic kidney disease, accounting for approximately 20%-25% of cases globally. In obesity-related kidney disease (OKD), ectopic lipid accumulation in renal proximal tubule cells impairs autophagic flux, exacerbating kidney injury. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, such as dapagliflozin, induce a fasting-like metabolic state and increase circulating β-hydroxybutyrate (β-HB) levels. However, the role of β-HB in modulating autophagic flux in OKD remains unclear. To investigate the potential involvement of β-HB in the renoprotective effects of dapagliflozin, diet-induced obesity (DIO) mice were used. Twelve DIO mice maintained on a high-fat diet (HFD) were randomly assigned to receive dapagliflozin or the β-HB precursor 1,3-butanediol (n = 6 per group). For each treatment, six DIO mice on HFD served as experimental models and were compared with six age-matched mice fed a standard chow diet as controls. Our study showed that dapagliflozin treatment significantly increased plasma β-HB levels and improved metabolic profiles in DIO mice. Exogenous ketone supplementation elicited similar metabolic and renoprotective effects. Both interventions enhanced autophagic flux in proximal tubule cells and attenuated structural damage in glomeruli and tubules. The renoprotective effects of dapagliflozin were associated with improved autophagic flux, suggesting that elevated β-HB levels may contribute to these benefits. The data suggest that dapagliflozin improves autophagic flux in OKD, potentially mediated by increased plasma β-HB levels. These findings provide insight into the metabolic mechanisms underlying SGLT-2 inhibitor-mediated renoprotection and highlight β-HB as a possible therapeutic target in OKD.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"17 1","pages":"479-491"},"PeriodicalIF":4.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0